In the initial investigation of this thesis, Fick's second law of diffusion was modified to describe both the transient, and the steady-state, transdermal transport of hydrophilic permeants through unbranched, aqueous pore channels. This new transport model, combined with dual radiolabeled diffusion experiments, was then used to separately evaluate how the porosity, the tortuosity, and the hindrance factor of the aqueous pore channels that exist in the skin varied as the extent of skin perturbation due to simultaneous treatment of the skin with low-frequency ultrasound (US) and a chemical enhancer, the surfactant sodium lauryl sulfate (SLS), and as the radius of the hydrophilic permeant delivered across the skin, were increased. This investigation revealed that the values of the hindrance factor and of the tortuosity decreased as the radius of the hydrophilic permeant increased, and that the value of the porosity of the aqueous pore channels increased as the extent of skin perturbation due to the application of US increased. This last result suggested that low-frequency US primarily enhances the transport of hydrophilic permeants by increasing the fraction of the skin surface occupied by the aqueous pore channels.(cont.) This modeling approach was next applied to the passive delivery of hydrophobic permeants through the branched pathways located in the intercellular lipid bilayer domain of untreated stratum corneum (SC), the outermost layer of the skin. The existence of these branched pathways led to the development of a new theoretical model, the Two-Tortuosity Model, which requires two tortuosity factors to account for: 1) the effective diffusion path length, and 2) the total volume of the branched, intercellular transport pathways, both of which may be evaluated from known values of the SC structure. After validating the Two-Tortuosity model with simulated SC diffusion experiments in FEMLAB (a finite element software package), the vehicle-bilayer partition coefficient, Kb, and the lipid bilayer diffusion coefficient, Db, in untreated human SC were evaluated using this new model for two hydrophobic permeants, naphthol (Kb = 233 + 44, Db = 1.6*10-7 + 0.3*10-7 cm2/s) and testosterone (Kb = 100 + 14, Db = 1.8*10-8 + 0.2*10-8 cm2/s). This investigation demonstrated that the new proposed method to evaluate Kb and Db is more direct than previous methods, in which SC permeation experiments were combined with octanol-water partition experiments, or with SC solute release experiments, to evaluate Kb and Db.(cont.) Previous studies on ultrasound-mediated transdermal drug delivery had hypothesized that the discrete regions which form on the surface of skin treated with low-frequency US in the presence of a colored permeant are regions of high permeability. To test this hypothesis, full-thickness pig skin was treated simultaneously with low-frequency US and SLS in the presence of a hydrophilic fluorescent permeant, sulforhodamine B (SRB), which was used to observe the location of the hypothesized localized transport regions (LTRs) and of the surrounding regions of US-treated skin (the non-LTRs). After US-pretreatment, diffusion masking experiments, a novel experimental method in which hydrophobic vacuum grease was selectively applied to the skin surface, demonstrated that the permeability of calcein, another hydrophilic fluorescent permeant, in the LTRs was -80-fold greater than in the non-LTRs. Furthermore, measurements of the skin electrical resistivity in both the LTRs and the non-LTRs revealed significant decreases relative to the skin electrical resistivity in untreated skin (-5000-fold and -170-fold, respectively), suggesting that two levels of significant structural perturbation exist in skin treated simultaneously with ultrasound and SLS.(cont.) Finally, an analysis of the porosity-to-tortuosity ratio values suggested that transcellular transdermal transport pathways exist within the LTRs. To confirm the results of the previous investigation, the transdermal delivery of SRB and of rhodamine B hexyl ester (RBHE), a fluorescent hydrophobic permeant, in skin treated with low-frequency ultrasound (US) and/or a chemical enhancer (SLS) relative to untreated skin (the control) was analyzed with dual-channel two-photon microscopy (TPM). An analysis of the average fluorescence intensity profiles as a function of skin depth, obtained from the TPM images, revealed that SRB and RBHE penetrated beyond the stratum corneum and into the viable epidermis only in the LTRs of US-treated and of US/SLS-treated skin. Further analysis of the average fluorescence intensity profiles and of the enhancements in the vehicle-skin partition coefficient, the intensity gradient, and the effective diffusion path length confirmed that a chemical enhancer was required in the coupling medium during US-treatment to obtain two significant levels of increased penetration of SRB and RBHE into the skin.(cont.) Finally, by comparing the heights and the widths of the fluorescence intensity peaks obtained from the dual-channel TPM images, the existence of transcellular pathways was confirmed in the LTRs of US-treated and of US/SLS-treated skin for SRB and RBHE, as well as in SLS-treated skin for SRB. In the final investigation of this thesis, the differences in the hindrance factor, the porosity, and the tortuosity of the aqueous pore channels located in the LTRs and in the non-LTRs were evaluated for the delivery of four hydrophilic permeants (urea, mannitol, raffinose, and inulin) using the transport model developed in the initial investigation of this thesis combined with dual radiolabeled diffusion masking experiments. In this analysis, three different idealized cases were examined. In the first case, where the porosity and the tortuosity were assumed to be independent of the permeant radius, the hindrance factor, and, therefore, the average pore radius, was found to be statistically larger in the LTRs than in the non-LTRs. In the second case, where a distribution of pore radii was assumed to exist in the skin, no meaningful results could be obtained due to the large variation in the shape of the distribution of pore radii used in the analysis.(cont.) In the final case, where infinitely large aqueous pores were assumed to exist in the skin, the value of the porosity of the LTRs was found to be 3- to 8-fold larger than that of the non-LTRs, while there little difference was found in the values of the tortuosity of the LTRs and of the non-LTRs.